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Rodent models of behavior used in the fields of neuroscience and psychology generate a wealth of multimodal data. For instance, as a rodent moves and behaves in its environment, muscle contractions apply subtle forces to any surface the animal contacts. These forces generate acoustic waves that propagate through the waveguide as Lamb and shear horizontal (SH) waves and contain information about the rodent's physiology, behavior, and underlying psychological state. If the information in these waves were to be tapped, it would provide a novel, non-invasive way to study rodent behavior. This article lays the foundations for using guided ultrasonic waves generated by a mouse's movement on an aluminum plate for detecting behavior and drawing inferences about acoustic startle responses. The experimental setup involves piezoelectric sensors capturing the waves generated by the rodent's movement, which are then stored as discrete acoustic emission (AE) hits using an amplitude threshold-based data acquisition system. This method of data acquisition ensures that data collection occurs only when the animal moves or behaves, and each movement/behavior is represented by values of features within the generated wavepackets (AE hits). Through open field tests with C57BL/6J mice, utilizing piezoelectric sensors and the DAQ system, it was observed that every movement/behavior of the animal generated Lamb wavepackets within the frequency range of 20 kHz to 100 kHz. Furthermore, rearing behavior in the animals also led to the generation of SH wavepackets in the frequency range of 75 kHz to 230 kHz. This criterion was subsequently employed to detect rearing behavior. In the acoustic startle response test, where the animals' responses to intense sound pulse were recorded, AE hits' features proved useful in quantifying the response. These experimental findings validate the proposed technology's practicality and demonstrate its capability to enhance studies of rodent behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rats emit ultrasonic vocalizations (USV). During aversive situations, rats emit 22-kHz USV, which are considered "alarm calls" and supposed to reflect a negative affective state of the sender. During appetitive situations, rats emit 50-kHz USV, which are believed to reflect a positive affective state. Here, we recorded USV emission in adult male rats during the acoustic startle response test. Our results indicate varied USV emission in both the 22- and 50-kHz USV ranges. Enhanced startle responses were observed in rats with a predominant 22-kHz call profile, supporting the notion that 22-kHz USV emission is associated with a negative affective state., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest at any stage of the project., (Copyright © 2023. Published by Elsevier Inc.)

Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear-conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women., Competing Interests: Conflict of interest The authors report no conflict of interest. JD reports US patent 11,559,231 issued on 1.24.2023 entitled: System and method for determining a discrimination index for fear-potentiated startle., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Pimavanserin is a highly selective 5-HT 2A inverse agonist in current medical use. Prior studies suggest that 5-HT 2A serotonin receptors may play a role in anxiety and emotional memory. Therefore, pimavanserin was tested in a rat model of PTSD to determine whether it might ameliorate PTSD-like symptoms. The lifetime prevalence of PTSD is estimated to be 125% higher in women than men. Consequently, in an effort to create a robust model of PTSD that was more representative of human PTSD prevalence, 20-week old female rats of the emotionally hyperreactive Lewis strain were used for these studies. The rats were single-housed and exposed twice to restraint stress coupled with predator odor or to a sham-stressed condition. Twenty days after the second stress or sham-stress exposure, rats were injected with saline alone or with 0.3 or 1.0 mg/kg pimavanserin, doses that were confirmed to substantially block 5-HT 2A receptor activity in this study without causing any non-specific behavioral or adverse effects. One hour later, rats were tested for anxiety through acoustic startle response, the elevated plus-maze and three parameters of open field behavior. Five days later, blood was sampled for plasma corticosterone. The stressed/saline-injected rats had higher anxiety scores and corticosterone levels than sham-stressed/saline-injected rats. Pimavanserin significantly and generally dose-dependently reversed these persistent stress effects, but had no significant effect on the behavioral measures in normal, non-stressed rats. These results, consistent with a role for the 5-HT 2A receptor, suggest that pimavanserin might have potential to reduce some consequences of traumatic stress., Competing Interests: Declaration of competing interest Supported by funding from Acadia Pharmaceuticals Inc. to the University of Houston-Clear Lake, and by the University of Houston-clear Lake Biobehavioral Research Fund. Co-author Ethan S. Burstein is an employee of Acadia Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Women with a history of adverse childhood experiences (ACEs) enter pregnancy and the postpartum with a physiologic system programmed by early life stress, potentially reflected in psychophysiologic reactivity., Methods: We enrolled pregnant, psychiatrically healthy women ≥18 years old. Using the ACE Questionnaire, women were categorized as high (≥2 ACEs; n = 77) or low ACE (<2 ACEs; n = 72). Participants completed an affective modulation of acoustic startle response (ASR) task during pregnancy and postpartum, in which ASR magnitude was measured while participants viewed pleasant, unpleasant, and neutral pictures. Two types of control trials were included (habituation trials presented at baseline and intertrial interval trials presented when no picture was present)., Results: Among high ACE women, ASR was significantly higher postpartum compared with pregnancy in the unpleasant (p = 0.002, β = 0.46, 95% CI [0.18, 0.74], χ 2  = 10.12, z = 3.18) and intertrial interval trials (p = 0.002, β = 0.44, 95% CI [0.16, 0.73], χ 2  = 9.25, z = 3.04), accounting for multiple comparisons using a Bonferroni correction at p < 0.005. Among low ACE women, ASR was similar in pregnancy and postpartum., Conclusions: Physiological reactivity increased in high ACE women from pregnancy to postpartum, but no change was observed in low ACE women., Competing Interests: Declaration of Competing Interest L.H. consults to PureTech Health. C.N.E. consults to Asarina Pharma and Sage Therapeutics and receives research support from Sage Therapeutics. All other authors report no declarations of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Recently, we demonstrated that the peak-end memory bias, which is well established in the context of pain, can also be observed in anxiety: Retrospective evaluations of a frightening experience are worse when peak anxiety is experienced at the end of an episode. Here, we set out to conceptually replicate and extend this finding with rigorous experimental control in a threat of shock paradigm. We induced two intensity levels of anxiety by presenting visual cues that indicated different strengths of electric stimuli. Each of the 59 participants went through one of two conditions that only differed in the order of moderate and high threat phases. As a manipulation check, orbicularis-EMG to auditory startle probes, electrodermal activity, and state anxiety confirmed the effects of the specific threat exposure. Critically, after some time had passed, participants for whom exposure had ended with high threat reported more anxiety for the entire episode than those for whom it ended with moderate threat. Moreover, they ranked their experience as more aversive when compared to other unpleasant everyday experiences. This study overcomes several previous limitations and speaks to the generalizability of the peak-end bias. Most notably, the findings bear implications for exposure therapy in clinical anxiety., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Automatic sensor-to-foot alignment is required in clinical gait analysis using inertial sensors to avoid assumptions about sensors initial positions and orientations. Numerous studies have proposed alignment methods. The current study aimed at describing and accessing the performance of a simple rule to automatically recognize the orientation of the sagittal plane foot angular velocity that can be used with any alignment method and any populations including individuals with severe motor disorders such as patients with cerebral palsy (CP). Fifty-five participants (15 healthy, 15 with CP and 25 with various other motor disorders) wore IMUs on both feet during one or several visits of clinical gait analysis (CGA) with optical motion capture system as reference. The foot coordinate system was determined using acceleration during motionless periods and angular velocity during walking, as previously described in the literature. Based on the foot sagittal plane angular velocity, a novel rule is introduced to determine the latest uncertainty related to mediolateral axis direction which often causes errors. It consisted of massively filtering the signal and applying a simple peak detection, omitting the double peaks with the same sign. The time between the negative and positive peaks can inform on the axis direction. This verification showed excellent results with 99,94% sensibility against the reference. This simple rule could be used to further improve existing sensor-to-segment algorithms with inertial sensors located on the feet, and thus improve pathological gait analysis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in many clinical conditions, including schizophrenia. The inbred Roman high-avoidance (RHA) rats, compared to their low-avoidance (RLA) counterparts, show distinct schizophrenia-like phenotypes, such as spontaneous deficits in PPI accompanied by decreased medial prefrontal cortex (mPFC) activity and volume. Schizophrenia-like deficits are usually attenuated by antipsychotic drugs, but these drugs often produce severe side effects. In order to reduce these side effects, the neuropeptide oxytocin has been proposed as an alternative natural antipsychotic for schizophrenia. Here, we examined the effects of peripheral oxytocin administration (saline, 0.04, and 0.2 mg/kg) on PPI in the RHA vs. RLA rats, as well as in the outbred heterogeneous stock (HS) rats. Our results showed that oxytocin increased PPI in the HS rats and attenuated PPI deficits in the RHA rats, but it did not significantly affect PPI in the RLAs. To explore whether these divergent effects were associated with differences in oxytocinergic mechanisms, we analyzed gene expression of the oxytocin receptor (OXTR) and the regulator of oxytocin release (CD38) in the mPFC of the Roman rats. Consistent with the differential oxytocin effects on PPI (RHA > RLA), constitutive CD38 expression was reduced in the RHA rats compared to the RLAs, while oxytocin administration increased OXTR expression in both strains. Overall, the present work reveals that oxytocin administration shows antipsychotic-like effects on PPI in outbred and inbred rats, and it suggests that these effects may be related to basal differences in oxytocin-mediated mechanisms in the mPFC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It is unclear whether all animal models of anxiety-like states developed using males are appropriate for use in females. In females, tests involving a learning component might be influenced not only by estrous cycle stage on the test day but also by the stage during the conditioning process. We used two tests - conditioned freezing (CF) and fear potentiated startle (FPS) to compare responsiveness of male rats and females conditioned and/or tested in proestrus (P) or late diestrus (LD). For CF all rats displayed a similar freezing response regardless of sex or estrous cycle stage. In terms of FPS, males and females conditioned in P and tested in P or LD, and females conditioned in LD and tested in LD all showed potentiated startle. The response waned during the test session in males and in females conditioned in P, but not in those conditioned in LD. In contrast, FPS was not apparent in the first half of the test session in females conditioned in LD and tested in P but developed in the second half. We suggest that fear learning during P and LD is robust but may be initially be obscured in rats tested in P because of generalization to the CS due to high estrogen. Estrous cycle stage is an important consideration which must be taken into account in designing behavioural tests in females., (Copyright © 2021. Published by Elsevier Inc.)

Excessive avoidance behaviour is a cardinal symptom of anxiety disorders. Avoidance is not only associated with the benefits of avoiding threats, but also with the costs of missing out on rewards upon exploration. Psychological and psychophysiological mechanisms contributing to these costly avoidance decisions in prospect of mixed outcomes remain unclear. We developed a novel Fearful Avoidance Task (FAT) that resembles characteristics of real-life approach-avoidance conflicts, enabling to disentangle reward and threat effects. Using the FAT, we investigated individual differences in avoidance behaviour and anticipatory psychophysiological states (i.e. startle reflex and skin conductance) in a relatively large sample of 343 (78 females) participants. Avoidance under acute threat of shock depends on a trade-off between perceived reward and threat. Both increased startle and skin conductance in the absence of threat of shock emerged as predictors of increased avoidance (potentially indicative of fear generalization). Increased avoidance was also associated with female sex and trait anxiety, dependent on reward and threat levels. Our findings highlight distinct possible predictors of heightened avoidance and add to mechanistic understanding of how individual propensity for costly avoidance may emerge. Distinct avoidance typologies based on differential reward and threat sensitivities may have different mechanistic origins and thereby could benefit from different treatment strategies., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The ability to update responding to threat cues is an important adaptive ability. Recently, Morriss et al. (2019) demonstrated that participants scoring high in Intolerance of Uncertainty (IU) were more capable of threat reversal. The current report aimed to conceptually replicate these results of Morriss et al. (2019) in an independent sample using a comparable paradigm (n = 102). Following a threat conditioning phase, participants were told that cues associated with threat and safety from electric shock would reverse. Responding was measured with skin conductance and fear potentiated startle. We failed to conceptually replicate the results of Morriss et al. (2019). Instead, we found that, for participants who received precise contingency instructions prior to acquisition, lower IUS (controlling for STAI-T) relative to higher IUS was associated with greater threat reversal, indexed via skin conductance responses. These results suggest that IU and contingency instructions differentially modulate the course of threat reversal., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although memory of past experiences is crucial for the ability to transfer knowledge to new situations, surprisingly little research has directly investigated the relationship between memory and generalization. The present study sought to investigate how the perceptual memory of a trained stimulus influences generalization to similar stimuli. Forty participants underwent a fear conditioning procedure on Day 1, and separate memory recall and generalization tests on Day 2. We focused on two aspects of perceptual memory: namely memory bias (i.e., over- or underestimation of stimulus magnitude) and uncertainty. We found that memory bias predicted the pattern of generalized self-reported (expectancy ratings) and psychophysiological responses (fear-potentiated startle responses). Memory uncertainty was measured in two ways: self-reported uncertainty ratings and variability in stimulus recall. We found that higher levels of self-reported memory uncertainty corresponded with a broader generalization gradient on US expectancy, while greater variability in memory recall was associated with a broader generalization gradient on fear-potentiated startle responses. Taken together, our findings suggest that memory is an important determinant of generalized behavior and illustrate the need to account for these interindividual differences in perceptual memory when examining the generalization of learned responses., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Resilience, the degree to which individuals are physiologically and behaviourally impacted by stressors, can be enhanced by positive experiences (e.g. positive moods in human, environmental enrichment in rodents). Such effects are important for human health, but could also have important animal welfare implications in terms of farm, laboratory and zoo animals' abilities to cope with stressors. Here we investigated whether enrichments can increase resilience in chickens, the world's most abundant agricultural animal. The stress reactivity of laying hens housed for 5-6 weeks in enriched environments was compared to that of controls housed in smaller, emptier, less preferred pens, via: 1) startle reflex amplitudes to an abrupt, intense sensory stimulus (a light flash); and 2) autonomic responses to restraint and the sudden appearance of a novel object, assessed from decreases in comb temperature. Startle amplitudes were consistently reduced in the enriched hens, exerted with around one sixth the force seen in control hens. Maximum comb temperature decreases, and latencies for comb temperatures to return to prestress levels, also both fell by around a third. Enrichment thus reduced hens' intrinsic behavioural and physiological responses to standardized stressors (doing so even outside the home pen), just as occurs in laboratory rodents. Enrichment also reduced baseline comb temperature, suggesting that this could be a non-invasive indicator of welfare. Altered judgment biases did not seem to be the mechanism. Further work should now investigate the processes underlying the apparently enhanced stress resilience of animals housed in preferred conditions, and also investigate baseline comb temperature as a chronic stress indicator in poultry., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fear of physical activity (FoPA) has been suggested as a barrier to physical activity in patients with heart failure and might be associated with low adherence to exercise regimen despite medical guideline recommendations. The present study examined physiological indicators of FoPA by assessing startle modulation (via EMG at the orbicularis oculi muscle) and heart rate responses (derived from ECG) after affective priming with lexical stimuli of positive, neutral, and negative valence, as well as words related to physical activity as potentially phobic cues. After screening for FoPA in patients with heart failure and healthy adults, twenty participants each were assigned to one of three subsamples: a healthy control group and two cardiac patient groups scoring either low or high on FoPA. The high-FoPA group showed startle potentiation and more pronounced heart rate acceleration (than did controls) in the phobic prime condition, indicating defensive response mobilization. Among the patients, higher FoPA accounted for 30% of the startle potentiation by phobic priming, whereas general anxiety, depression, and disease severity were no significant predictors of startle modulation. These findings suggest that FoPA in patients with heart failure is associated with defensive responses on a physiological level that might be indicative of avoidance behavior, thereby contributing to low adherence to exercise regimen. Thus, FoPA presents a significant target for psychological interventions to foster physical activity in cardiac patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Vitamin D has been shown in a wide variety of species to play critical roles in neurodevelopment. Vitamin D deficiency disrupts development of the brain and can cause lasting behavioral dysfunction. Zebrafish have become an important model for the study of development in general and neurodevelopment in particular. Zebrafish were used in the current study to characterize the effects of developmental vitamin D deficiency on behavioral function. Adult zebrafish that had been chronically fed a vitamin D deficient or replete diets were bred and the offspring were continued on those diets. The offspring were behaviorally tested as adults. In the novel tank diving test the vitamin D deficient diet significantly lowered the vertical position of fish indicative of more anxiety-like behavior. In the novel tank diving test swimming activity was also significantly decreased by vitamin D deficiency. Startle response was increased by developmental vitamin D deficiency during the early part of the test. No significant effects of vitamin D deficiency were seen with social affiliation and predatory stimulus avoidance tests. These results indicate a phenotype of vitamin D deficiency characterized by more anxiety-like behavior. This result was relatively specific inasmuch as few or no behavioral effects were seen in other behavioral tests., Competing Interests: Declaration of Competing Interests None., (Copyright © 2020. Published by Elsevier Inc.)

There are indications that exposing adolescent rodents to oxytocin (OT) promotes social activity and reduces anxiety in adulthood. Adult male gray rats selected for elimination and enhancement of the aggressive response to humans, when exposed to OT, showed divergent changes in the resident behavior towards the intruder. It could be assumed that adolescent administration of both OT and antagonist of OT receptor (OTR) would also have different long-term effects on resident behavior and startle reflex in adult aggressive and tame rats. The aim of this work is to study the long-term effects of adolescent administration of both OT and antagonist of OT receptor (OTR) on resident behavior and startle reflex in adult tame and aggressive male gray rats. Starting at the age of 28 days, the animals received nasal applications of 5 μL of oxytocin solution (1 μg / μL) or saline for 5 days (daily). At the age of two months, the acoustic startle amplitude was assessed in two series of 5 acoustic stimuli. The resident-intruder test was performed one week later. Antagonist of OT receptor l-368,899 was administered intraperitoneally (i.p.) once at a dose of 5 mg/kg at the age of 30-33 days. Subsequent startle reflex tests were performed 20 days later, at the age of 50-53 days. A week later, the resident-intruder test was performed on the same rats. The startle amplitude in aggressive rats of the control group (in two series of acoustic stimuli) and those having received saline (in the first series) was larger than in the corresponding tame groups. Oxytocin and saline solutions did not significantly affect the startle amplitude compared to control animals. After saline administration, the attack latency in tame rats was longer than in aggressive rats (P <0.05). Oxytocin treatment caused a prolongation of this period in aggressive males compared with control animals receiving saline solution (P <0.01). In addition, oxytocin administration in aggressive males caused an increase in the time of social behavior, which did not include aggressive and same-sex behavior, as compared with the corresponding control animals (P <0.05). Exogenous oxytocin receptor antagonist (l-368,899) did not affect the startle amplitude and behavior in the resident-intruder test in aggressive and tame male rats. Adolescent OT treatment causes a prolongation of both the attack latency and social behavior in the resident-intruder test in adult aggressive male rats, but does not affect these parameters in tame rats., Competing Interests: Declaration of Competing Interests The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigated the perception of two mechanoreceptive modalities alone and in combination: main effects and interaction between auditory and somatosensory stimulation in mice. Fifteen C57BL/6J mice between the ages of 1 and 6 months were tested three times each. Experimental design roughly followed published procedures using pre-pulse inhibition (PPI) of the acoustic startle response, except pre-pulses included vibration of the test chamber as well as soft sounds. Auditory pre-pulses were 80 dB broadband noises of 4, 9, 25, or 45 ms duration. Vibrations were of the same duration but of different frequencies (500, 460, 360, and 220 Hz). Pre-pulse inhibition increased with duration of the auditory pre-pulses, as expected. There was significant PPI to some but not all vibrotactile pre-pulses. Multimodal PPI was approximately additive (no significant auditory-by-somatosensory interaction). PPI increased more with age to somatosensory than to auditory pre-pulses. Future studies of multi-modal psychophysics in various mouse mutants could lend support to more mechanistic studies of neural specificity and possibly autism, tinnitus, and PTSD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Noise-exposed rat pups provide a model of early deprivation of sensory input to the central auditory system, allowing the study of developmental neuroplasticity. Our previous results have demonstrated that a brief exposure of rats to broadband noise (125 dB SPL 8 min, 14th postnatal day) at the onset of hearing resulted in an altered intensity perception and frequency discrimination in adulthood despite normal hearing thresholds. In this study, we assessed the gap-detection ability and possible presence of tinnitus- and hyperacusis-like behavior in adult rats after the same neonatal acoustic trauma, using measurements of the acoustic startle response (ASR) in quiet and noisy environments and its prepulse inhibition by gaps in noise (gap-PPI). A significant deficit in the ability to detect gap was observed in the exposed rats when 55 dB SPL broadband noise was used as background. An increase of noise intensity to 65-75 dB SPL led to strengthening of the gap-PPI in exposed animals, which approached the gap-PPI values of control animals at these levels. Behavioral signs of tinnitus (gap detection deficits in 10 kHz narrow band noise) were found in 25% of exposed rats. An increased sensitivity to continuous noise was manifested in all exposed rats by suppression of the ASR at significantly lower background noise levels than in the controls. This effect was particularly pronounced in rats with tinnitus-like behavior. Our results indicate that neonatal acoustic trauma, producing only a transient threshold shift, may produce permanent abnormalities in suprathreshold auditory functions and the development of tinnitus and hyperacusis-like behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fear conditioning and extinction have been implicated in the etiology and maintenance of anxiety disorders. Most fear conditioning studies have been conducted with adult samples and the few published developmental studies in clinically anxious youth have yielded inconsistent results. The aim of the current review was to use meta-analysis to examine possible differences in fear conditioning and extinction in clinically anxious and non-anxious youth. Seven fear conditioning studies were included in the analysis, with a total of 160 clinically anxious and 166 non-anxious youth. All the studies included in the meta-analysis used a differential conditioning paradigm with at least one or more of the primary dependent variables: self-reported fear, skin conductance response (SCR) and fear potentiated startle (FPS). Similar differential fear acquisition and extinction patterns were observed in anxious and non-anxious individuals. However, anxious youth exhibited stronger fear responses to individual stimuli compared to their non-anxious counterparts. Results in clinically anxious youth resemble those reported in previous studies with clinically anxious adults. Importantly, due to the small number of fear learning studies conducted among youth, these results should be interpreted with caution. Further research is needed so as to better understand fear acquisition and extinction processes in developmental populations. In addition, future studies should focus on other fear-related learning processes such as differences in return of fear, retrieval of fear memory and more subtle differences in fear generalization., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Prepulse inhibition (PPI) can be modulated by both the Val158Met (rs4680) polymorphism of the Catechol-O-Methyltransferase (COMT) gene and the menstrual-cycle-related hormone fluctuations, each of which affects the subcortical/cortical dopamine metabolism. PPI can also be modulated by attention. The attentional modulation of PPI (AMPPI) is sensitive to psychoses. Whether the Val158Met polymorphism affects the AMPPI in female adults at different menstrual-cycle phases is unknown. This study examined whether AMPPI and/or PPI are affected by the Val158Met polymorphism in 177 younger-adult females whose menstrual cycles were mutually different across the menstruation, proliferative, or secretory phases. The AMPPI was evaluated by comparing PPI under the condition of the auditory precedence-effect-induced perceptual spatial separation between the prepulse stimulus and a masking noise (PPI PSS ) against that under the condition of the precedence-effect-induced perceptual spatial co-location (PPI PSC ). The results showed that both the menstrual cycle and the COMT Val158Met polymorphism affected both PPI PSC and PPI PSS , but not the AMPPI (difference between PPI PSS and PPI PSC ). Moreover, throughout the menstrual cycle, both PPI PSC and PPI PSS decreased monotonously in Val/Val-carrier participants. However, the decreasing pattern was not overserved in either Met/Met-carrier or Met/Val-carrier participants. Thus, in healthy younger-adult females, PPI PSC and PPI PSS , but not the AMPPI, is vulnerable to changes of ovarian hormones, and the COMT Val158Met polymorphism also has a modulating effect on this menstrual-cycle-dependent PPI variation. In contrast, the AMPPI seems to be more steadily trait-based, less vulnerable to ovarian hormone fluctuations, and may be useful in assisting the diagnosis of schizophrenia in female adults., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Fear extinction studies in youth have yielded mixed results due to developmental processes and variations in design, methodology and dependent measures. This systematic review focused on studies with healthy youth between 2 and 17 years of age to identify experimental parameters of studies documenting extinction effects. Thirty-five studies met inclusion criteria and the following themes emerged (a) some studies employed parameters and task demands that are complex and require active participant involvement whereas others involved simple stimulus configurations and passive participant involvement, and (b) variation exists among dependent measures in units of measurement, timing and type of measurement. The review identified that studies using geometric shape conditioned stimuli (CS) paired with a tone unconditioned stimulus (US) (e.g., metal scraping on slate), as well as face CSs with a scream US produced the most reliable extinction effects, although the latter combination may be associated with higher drop-out than shape CSs and a tone US. The most commonly used and effective dependent measures for revealing extinction effects were skin conductance responses (SCR) and subjective ratings (SR) of CS valence, fearfulness and arousal. Fear potentiated startle (FPS) blink reflexes were also an effective but less commonly used measure. It is recommended that future studies use shape CSs and the metal scraping on slate US in studies involving children and either shape CSs and the metal scraping on slate US or face CSs paired with a scream US with adolescents. It is also recommended that US expectancy ratings and CS evaluations are assessed trial-by-trial and between-phase, and that startle-eliciting stimuli to measure startle blink reflexes are delivered on every second trial per CS so that SCR and FPS can be examined. However, further research is required to determine whether increased participant involvement due to providing trial-by-trial and between-phase ratings of the CSs and US differentially influences responding, particularly in children relative to adolescents and adults., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Epidemiological studies suggest that binge drinking is prevalent among adolescents, and may result in neurobehavioral consequences. Animal models provide the experimental control to investigate the consequences of "binge" alcohol exposure during this neurodevelopmental epoch. The current study used an animal model that combined an intermittent pattern of alcohol vapor exposure with voluntary drinking of 20% unsweetened alcohol in adolescent male and female Wistar rats (postnatal day [PD] 22-62), in order to test for potential differences in behavioral changes, ethanol drinking, and hypocretin/orexin (Hcrt/OX) signaling associated with exposure status. Two weeks after discontinuation of the alcohol vapor exposure and drinking during adolescence, rats were tested in adulthood for anxiety-like behaviors using a modified open-field conflict task, pre-pulse facilitation of startle response, light/dark box, and marble burying test. Adolescent alcohol exposure led to overall decreased startle response and increased behavioral arousal in the light/dark chamber during adulthood. Additionally, male rats demonstrated more disinhibited behavior during the conflict task compared to females, and female rats exhibited more rearing behavior during the light/dark test. Rats were also given a 2-bottle choice test that resulted in adolescent alcohol-exposed rats drinking significantly more alcohol in adulthood. Further, female rats also consumed more alcohol in adulthood compared to males. Estrous cycle phase did not account for any of the sex differences observed in the behavioral measures. Histological results indicated that adolescent alcohol did not alter Hcrt/OX-1 or Hcrt/OX-2 receptor mRNA expression levels in adult rats compared to control adults. However, female rats expressed a higher level of Hcrt/OX-1 and Hcrt/OX-2 receptor mRNA in the frontal cortex compared to males. These data suggest that our current model of intermittent ethanol exposure in adolescence can modestly affect both behavior and future consumption of alcohol and that Hcrt/OX receptor signaling differs between males and females., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tinnitus alters auditory-somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory-somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. Here, we studied the expression of vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) in the CN, which reveals glutamatergic projections from the cochlea as well as somatosensory systems to this brainstem auditory center. Guinea pigs were unilaterally exposed to narrowband noise and behaviorally tested for tinnitus using gap-prepulse inhibition of the acoustic startle. Following physiological and behavioral measures, brain sections were immunohistochemically stained for VGLUT1 or VGLUT2. Puncta density was determined for each region of the ipsilateral and contralateral CN. Tinnitus was associated with an ipsilateral upregulation of VGLUT2 puncta density in the granule cell domain (GCD) and anteroventral CN (AVCN). Furthermore, there was a tinnitus-associated interaural asymmetry for VGLUT1 expression in the AVCN and deep layer of the dorsal CN (DCN3), due to contralateral downregulation of VGLUT1 expression. These tinnitus-related glutamatergic imbalances were reversed upon bimodal stimulation treatment. Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Recent reports demonstrate that DNA damage is induced, and rapidly repaired, in circuits activated by experience. Moreover, stress hormones are known to slow DNA repair, suggesting that prolonged stress may result in persistent DNA damage. Prolonged stress is known to negatively impact physical and mental health; however, DNA damage as a factor in stress pathology has only begun to be explored. Histone H2A-X phosphorylated at serine 139 (γH2AX) is a marker of DNA double-strand breaks (DSB), a type of damage that may lead to cell death if unrepaired. We hypothesized that a 14-day period of variable stress exposure sufficient to alter anxiety-like behavior in male C57BL/6J mice would produce an increase in γH2AX levels in the bed nucleus of the stria terminalis (BNST), a region implicated in anxiety and stress regulation. We observed that 14 days of variable stress, but not a single stress exposure, was associated with increased levels of γH2AX 24 h after termination of the stress paradigm. Further investigation found that phosphorylation levels of a pair of kinases associated with the DNA damage response, glycogen synthase kinase 3 β (GSK3β) and p38 mitogen-activated protein kinase (MAPK) were also elevated following variable stress. Our results suggest that unrepaired DNA DSBs and/or repetitive attempted repair may represent an important component of the allostatic load that stress places on the brain., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

The present study was designed to systematically assess the control experience routinely used in our laboratory as part of studies on predator odour stress. Specifically, we examined effects of the physical and social components of this control experience on measures of anxiety-like behaviour in adolescent rats. Adolescent animals are at increased susceptibility to environmental perturbations and have been used for such studies much less often. Long-Evans rats of both sexes were subjected to physical stimulation (Exposed or Unexposed) and social stimulation (Single-Housed or Pair-Housed), resulting in four groups. Exposed rats received six 30-min exposures to an enclosed arena containing an unscented piece of cat collar occurring between adolescence and early adulthood, while Unexposed remained in the home cage. Groups of Exposed and Unexposed animals were housed singly (Single-Housed) from early adolescence to early adulthood or Pair-Housed during this time. Experimental procedures began in adolescence and involved repeated assessment of startle amplitude (measure of anxiety-like behaviour) and prepulse inhibition (PPI; a measure of sensorimotor gating) to gauge the short-term impact of social and/or physical stimulation. All animals were re-paired in adulthood prior to a final startle/PPI session to assess if isolation limited to adolescence could impose long-term effects that were not reversible. We also measured anxiety-like behaviour in adulthood using an extended open field test (EOFT; addition of novel objects to the open field on later days), and the elevated plus maze task (EPM), as well as a sucrose preference test (SPT) to measure anhedonia. An absence of social or physical stimulation resulted in increased startle amplitude and some measures of anxiety-like behaviour in the EOFT, but a reduction in such anxiety-like behaviour in the EPM task. These results suggest common neural substrates for the physical and social experiences. Performance in the SPT was unaltered by any experimental treatments. Sensorimotor gating, as measured by PPI, was increased in the absence of physical stimulation with no short-term effect of isolation, or of re-pairing. These results indicate the importance of considering individual components of the rearing environment of rats, while showing the need to use multiple assays of anxiety-like behaviour., (Copyright © 2017. Published by Elsevier Inc.)

Background: Previous studies have suggested that fear memories can be updated when recalled, a process referred to as reconsolidation. Given the beneficial effects of model-based safety learning (i.e. vicarious extinction) in preventing the recovery of short-term fear memory, we examined whether consolidated long-term fear memories could be updated with safety learning accomplished through vicarious extinction learning initiated within the reconsolidation time-window. We assessed this in a final sample of 19 participants that underwent a three-day within-subject fear-conditioning design, using fear-potentiated startle as our primary index of fear learning., Methods: On day 1, two fear-relevant stimuli (reinforced CSs) were paired with shock (US) and a third stimulus served as a control (CS). On day 2, one of the two previously reinforced stimuli (the reminded CS) was presented once in order to reactivate the fear memory 10 min before vicarious extinction training was initiated for all CSs. The recovery of the fear memory was tested 24 h later., Results and Conclusion: Vicarious extinction training conducted within the reconsolidation time window specifically prevented the recovery of the reactivated fear memory (p = 0.03), while leaving fear-potentiated startle responses to the non-reactivated cue intact (p = 0.62). These findings are relevant to both basic and clinical research, suggesting that a safe, non-invasive model-based exposure technique has the potential to enhance the efficiency and durability of anxiolytic therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This study presents the first evaluation of the associations between responses in two paradigms related to schizophrenia in the genetically heterogeneous NIH-HS rat stock. NIH-HS rats are a stock of genetically heterogeneous animals that have been derived from eight different inbred strains. A rotational breeding schedule has been followed for more than eighty generations, leading to a high level of genetic recombination that makes the NIH-HS rats a unique tool for studying the genetic basis of (biological, behavioral, disease-related) complex traits. Previous work has dealt with the characterization of coping styles, cognitive and anxiety/fear-related profiles of NIH-HS rats. In the present study we have completed their characterization in two behavioral models, prepulse inhibition (PPI) and latent inhibition (LI) of the two-way active avoidance response, that appear to be related to schizophrenia or to schizophrenia-relevant symptoms. We have found that these rats display PPI for each of the four prepulse intensities tested, allowing their stratification in high, medium and low PPI subgroups. When testing these three subgroups for LI of two-way active avoidance acquisition it has been observed that the LowPPI and MediumPPI subgroups present impaired LI, which, along with the fact that the HighPPI group presents significant LI, allows us to hypothesize that responses in these two paradigms are somehow related and that selection of NIH-HS rats for Low vs HighPPI could make a promising animal model for the study of clusters of schizophrenia-relevant symptoms and their underlying neurobiological mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Anthropogenic (man-made) noise, a global pollutant of international concern, is known to affect the physiology and behaviour of a range of organisms. However, experimental studies have tended to focus on trait means; intra-population variation in responses are likely, but have rarely been explored. Here we use established experimental methods to demonstrate a condition-dependent effect of additional noise. We show that juvenile European eels (Anguilla anguilla) in good condition do not respond differently to playbacks of ambient coastal noise and coastal noise with passing ships. By contrast, the additional noise of ship passes caused an increase in ventilation rate and a decrease in startling to a looming predatory stimulus in poor condition eels. Intra-population variation in responses to noise has important implications both for population dynamics and the planning of mitigation measures., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We have a well-established animal model of PTSD composed of predator exposure administered in conjunction with social instability that produces PTSD-like behavioral and physiological abnormalities one month after stress initiation. Here, we assessed whether the PTSD-like effects would persist for at least 4months after the initiation of the psychosocial stress regimen. Adult male Sprague-Dawley rats were exposed to either 2 or 3 predator-based fear conditioning sessions. During each session, rats were placed in a chamber for a 3-min period that terminated with a 30-s tone, followed by 1h of immobilization of the rats during cat exposure (Day 1). All rats in the stress groups received a second fear conditioning session 10days later (Day 11). Half of the stress rats received a third fear conditioning session 3weeks later (Day 32). The two cat-exposed groups were also exposed to daily unstable housing conditions for the entire duration of the psychosocial stress regimen. The control group received stable (conventional) housing conditions and an equivalent amount of chamber exposure on Days 1, 11 and 32, without cat exposure. Behavioral testing commenced for all groups on Day 116. The stress groups demonstrated increased anxiety on the elevated plus maze, impaired object recognition memory and robust contextual and cued fear conditioned memory 3months after the last conditioning session. Combined data from the two stress groups revealed lower post-stress corticosterone levels and greater diastolic blood pressure relative to the control group. These findings indicate that predator-based psychosocial stress produces persistent PTSD-like physiological and behavioral abnormalities that may provide insight into the neurobiological and endocrine sequelae in traumatized people with PTSD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Experimental animals provide valuable opportunities to establish aetiological mechanisms and test new treatments for neurodevelopmental psychiatric conditions. However, it is increasingly appreciated that inter-strain differences cannot be neglected in the experimental design. In addition, the importance of including females in preclinical - but also clinical - research is now recognised. Here, we compared behaviour and prefrontal protein differences in male and female C57BL/6N and 129X1/SvJ mice as both are commonly used experimental rodents. Relative to 129X1/SvJ mice, both sexes of C57BL/6N mice had weaker sensorimotor gating, measured in the prepulse inhibition (PPI) of startle paradigm, and were more sensitive to amphetamine challenge in the open field. The pattern of protein expression in the prefrontal cortex of C57BL6N mice was also clearly distinct from 129X1/SvJ mice. Proteins differentially expressed were those associated with oxidative metabolism, receptor protein signalling, cell communication and signal transduction and energy pathways. We suggest that the C57BL/6N mouse may usefully proxy features of the neurodevelopmental disorders and could have application in pre-translational screening of new therapeutic approaches. The 129X1/SvJ strain in contrast, might be better suited to experimental studies of causal risk factors expected to lower PPI and increase amphetamine sensitivity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Our laboratory previously developed a novel neuropathic and inflammatory facial pain model for mice referred to as the Trigeminal Inflammatory Compression (TIC) model. Rather than inducing whole nerve ischemia and neuronal loss, this injury induces only slight peripheral nerve demyelination triggering long-term mechanical allodynia and cold hypersensitivity on the ipsilateral whisker pad. The aim of the present study is to further characterize the phenotype of the TIC injury model using specific behavioral assays (i.e. light-dark box, open field exploratory activity, and elevated plus maze) to explore pain- and anxiety-like behaviors associated with this model. Our findings determined that the TIC injury produces hypersensitivity 100% of the time after surgery that persists at least 21 weeks post injury (until the animals are euthanized). Three receptive field sensitivity pattern variations in mice with TIC injury are specified. Animals with TIC injury begin displaying anxiety-like behavior in the light-dark box preference and open field exploratory tests at week eight post injury as compared to sham and naïve animals. Panic anxiety-like behavior was shown in the elevated plus maze in mice with TIC injury if the test was preceded with acoustic startle. Thus, in addition to mechanical and cold hypersensitivity, the present study identified significant anxiety-like behaviors in mice with TIC injury resembling the clinical symptomatology and psychosocial impairments of patients with chronic facial pain. Overall, the TIC injury model's chronicity, reproducibility, and reliability in producing pain- and anxiety-like behaviors demonstrate its usefulness as a chronic neuropathic facial pain model., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Adolescent experiences of social deprivation result in profound and enduring perturbations in adult behavior, including impaired sensorimotor gating. The behavioral deficits induced by adolescent social isolation in rats can be ameliorated by antipsychotic drugs blocking dopamine D2 receptors in the prefrontal cortex (PFC) or by chronic administration of a cannabinoid CB1 receptor antagonist. The patterning and abundance of D2 receptors in the PFC evolves concurrently with CB1 receptors through the period of adolescence. This evidence suggests that mature expression and/or surface distribution of D2 and CB1 receptors may be influenced by the adolescent social environment. We tested this hypothesis using electron microscopic immunolabeling to compare the distribution of CB1 and D2 receptors in the PFC of adult male Sprague-Dawley rats that were isolated or socially reared throughout the adolescent transition period. Prepulse inhibition (PPI) of acoustic startle was assessed as a measure of sensorimotor gating. Social isolation reduced PPI and selectively decreased dendritic D2 immunogold labeling in the PFC. However, the decrease was only evident in dendrites that were not contacted by axon terminals containing CB1. There was no apparent change in the expression of CB1 or D2 receptors in presynaptic terminals. The D2 deficit therefore may be tempered by local CB1-mediated retrograde signaling. This suggests a biological mechanism whereby the adolescent social environment can persistently influence cortical dopaminergic activity and resultant behavior., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Early life stress is thought to enhance adult susceptibility to stress and stress-related mood disorders. In this study, fear-potentiated startle was used to model the acquisition of a traumatic event-related memory in female rats experiencing early life stress. Daily 1-hr maternal and sibling separation throughout day 2-9 postpartum (D2-9 PP) caused a decrease in the fear-potentiated startle, but not acoustic startle baseline, in adult female rats. The separation procedure did not affect corticosterone secretion but produced an increase in serum estradiol concentration. Moreover, the separation procedure did not affect histone 3 lysine 9 (H3K9) acetylation but decreased H3K9 mono- and tri-methylation in frontal cortices. Treatment with 5-aza-2'-deoxycytidine (AZA) (5mg/kg at alternative days from D2PP to D9PP or 10mg/kg at D5PP and D9PP), a DNA methylation inhibitor, did not affect the separation-decreased fear-potentiated startle. Treatment with valproic acid (VPA), a histone deacetylase inhibitor, at 3 dosing regimens (300mg/kg at D2-9PP; 100mg/kg at D2-4PP, 200mg/kg at D5-7PP, 300mg/kg at D8-9PP; 100mg/kg at D2-5PP, 200mg/kg at D6-9PP) prior to daily separation reversed such a decrease in fear-potentiated startle. The lowest effective VPA dosing regimen used (100mg/kg at D2-5PP, 200mg/kg at D6-9PP) reversed the separation-decreased H3K9 mono- and tri-methylation in frontal cortices. Eight-day VPA (300mg/kg/day) and AZA (5mg/kg/day) administrations starting at D28PP were ineffective in altering the separation-decreased fear-potentiated startle. We, hereby, suggest that decreased frontal cortical H3K9 mono- and tri-methylation may be involved in early life separation-decreased fear memory of adult rats., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We compared the effects of aversive and gentle handling in late pregnant ewes on fearfulness, heart rate variability and spatial learning in lambs. Twenty-four Norwegian-Dala ewes were studied. Ewes were subjected to gentle (i.e. soft talking and calm behavior) or aversive handling (i.e. swift movements and shouting) for 10 min twice a day during the last five weeks of pregnancy. Lambs from aversively (AVS) or gently (GEN) treated ewes were tested at 4 weeks of age. Lamb behavior was recorded during a) a human approach test, composed of 4 min of isolation and 4 min of exposure to an unfamiliar human, b) an umbrella startle test followed by 5-min recording, and c) two repetitions of a maze test. In addition, heart rate variability was recorded telemetrically before and after the human and startle tests. The baseline heart rate variability measures suggested a lower influence of vagal stimulation in AVS lambs. In the human approach test, AVS lambs vocalized and explored the environment less, and were slower to approach the human. They also tended to have higher flight distances during the startle test than the GEN lambs. The prenatal treatment had no significant effect in the maze test. In conclusion, we showed that aversive handling of pregnant ewes increased fearfulness and reduced vagal tone in their progeny compared to GEN lambs. These effects can have consequences for how lambs cope with rearing conditions., (Copyright © 2011 Elsevier Inc. All rights reserved.)

At present, exposure of a rodent to the odour of a predator is one of the most common animal models of post traumatic stress disorder (PTSD). Despite this, the model remains incompletely characterized, particularly in regard to within subject assessment of major PTSD-like behaviours. In an attempt to redress this situation, we have extensively characterized the two broad categories of behaviour that are considered to characterize PTSD, that is sensitized behaviours such as social withdrawal and hypervigilance and conditioned behaviours such as avoidance of trauma linked cues. Specifically, we determined the presence and duration of both conditioned and sensitized behaviours, in the same cohort of animals, after three exposures to predator odour. Conditioned fear was assessed on the basis of inhibition of locomotor activity upon return to context 2, 7, 14, 21, and 28 days after the last odour exposure session. To assess the impact on sensitization behaviours, we monitored acoustic startle responses and social interaction behaviour 4, 9, 16, 23, and 30 days after the last exposure session. In addition to examining the behavioural consequences associated with odour exposure, we also determined the key brain regions that were activated using DeltaFosB immunohistochemistry. Our results show that the two groups of behaviours thought to characterize PTSD (conditioned and sensitized) do not travel together in the predator odour model, with clear evidence of enduring changes in conditioned fear but little evidence of changes in social interaction or acoustic startle. With regard to associated patterns of activity in the brain, we observed that odour-exposed animals exhibited significantly higher numbers of FosB-positive nuclei in only the medial prefrontal cortex (mPFC), a finding that can be viewed as being consistent with the observed behavioural changes., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Sensorimotor gating, as measured by prepulse inhibition (PPI) of startle, is deficient in human beings with schizophrenia and is greatly reduced in rats after bilateral infusion of N-methyl-D-aspartate (NMDA) into the ventral hippocampus (VH). The disruption of PPI by bilateral VH NMDA infusion is blocked by bilateral medial prefrontal cortex (mPFC) lesions, but not by bilateral lesions of the fornix, which is the principal output pathway of the hippocampal formation of the VH. Tract-tracing studies have shown the presence of additional nonfornical pathways by which the VH and neighboring structures of the amygdala may reach forebrain regions that regulate PPI, including the mPFC. To determine whether these nonfornical pathways might mediate forebrain activation after VH NMDA infusion, we examined the effects of bilateral VH NMDA infusion on c-Fos protein expression in the mPFC and nucleus accumbens (NAC) after sham vs. bilateral fornix lesions. Significant increases of c-Fos expression were observed in both the mPFC and NAC after bilateral VH NMDA infusions. Fornix lesions blocked enhanced c-Fos expression in the NAC but not the mPFC after VH NMDA infusion. The results suggest that an intact fornix may be necessary for VH activation of the NAC, but that the VH uses additional nonfornical projections to activate PPI-regulatory circuits within the mPFC., (2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Social deprivation in early life disrupts emotionality and attentional processes in humans. Rearing rats in isolation reproduces some of these abnormalities, which are attenuated by daily handling. However, the neurochemical mechanisms underlying these responses remain poorly understood. We hypothesized that post-weaning social isolation alters the endocannabinoid system, a neuromodulatory system that controls emotional responding. We characterized behavioral consequences of social isolation and evaluated whether handling would reverse social isolation-induced alterations in behavioral reactivity to context and the endocannabinoid system. At weaning, pups were single or group housed and concomitantly handled or not handled daily until adulthood. Rats were tested in emotionality- and attentional-sensitive behavioral assays (open field, elevated plus maze, startle and prepulse inhibition). Cannabinoid receptor densities and endocannabinoid levels were quantified in a separate group of rats. Social isolation negatively altered behavioral responding. Socially-isolated rats that were handled showed less deficits in the open field, elevated plus maze, and prepulse inhibition tests. Social isolation produced site-specific alterations (supraoptic nucleus, ventrolateral thalamus, rostral striatum) in cannabinoid receptor densities compared to group rearing. Handling altered the endocannabinoid system in neural circuitry controlling emotional expression. Handling altered endocannabinoid content (prefrontal and piriform cortices, nucleus accumbens) and cannabinoid receptor densities (lateral globus pallidus, cingulate and piriform cortices, hippocampus) in a region-specific manner. Some effects of social isolation on the endocannabinoid system were moderated by handling. Isolates were unresponsive to handling-induced increases in cannabinoid receptor densities (caudal striatum, anterior thalamus), but were sensitive to handling-induced changes in endocannabinoid content (piriform, prefrontal cortices), compared to group-reared rats. Our findings suggest alterations in the endocannabinoid system may contribute to the abnormal isolate phenotype. Handling modifies the endocannabinoid system and behavioral reactivity to context, but surmounts only some effects of social isolation. These data implicate a pivotal role for the endocannabinoid system in stress adaptation and emotionality-related disturbances., (Published by Elsevier Ltd.)

The air-puff startle is an example of a simple behavior in mammals. Following the startle reaction, rats assume a defensive-like, immobile posture (DIP) of approximately 2-5 s in length. The aim of the present study was to examine the effect of bilateral lesions of the nucleus locus coeruleus/subcoeruleus (LC/SC) on the DIP. Using male Sprague-Dawley rats, the DIP period in the air-puff startle was measured with a digital stop watch. The DIP period was defined as the time between the application of the air-puff stimuli and the first motion after the startle reaction. For air-puff stimulation (14.4 psi in strength, 0.1 s in duration), compressed house air was presented as a transient through a vinyl tube suspended 2.5 cm above the rat's head. Two weeks before the experiment, the rats received bilateral injections of 6 microg of the neurotoxin 6-hydroxydopamine to specifically lesion noradrenaline-containing neurons of the LC/SC. In the sham-lesioned rats (n=8), the DIP period did not significantly alter compared with that before operation. In contrast, in the LC/SC-lesioned rats (n=9), the DIP period significantly reduced to 78% of the values before lesions. The results suggest that the LC/SC is involved in the development of the DIP. We speculate that the DIP period is an attentional state and vigilance condition because LC/SC neurons have been implicated in the regulation of the attentional state and vigilance., (2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Evidence suggests that exposure to bacterial endotoxin in early life can alter the production of pro-inflammatory cytokines in later life. This phenomenon may have significant consequences for pain and pain related behaviours as pro-inflammatory cytokines heighten pain sensitivity. This association has yet to be examined. As such, the aim of the present study was to characterize pain behaviours in adult rat offspring following prenatal endotoxin (PE) exposure. Pregnant F344 rats received endotoxin (200microg/kg, s.c.) or saline on gestational days 16, 18 and 20. Pain thresholds were assessed in the adult PE offspring (n=23) and control offspring (n=24) prior to and 4h following administration of lipopolysaccharide (LPS; 100microg/kg, s.c.). Three assays of pain were employed - the hot plate, tail immersion and von Frey tests. Results demonstrated sex-specific effects of prenatal endotoxin on the offspring, with PE males displaying unaltered pain thresholds on the von Frey test post-LPS administration (p<0.01), while male control offspring (n=24) displayed the expected hyperalgesia. Male PE offspring also displayed increased pain thresholds on the tail immersion test (p<0.01), while no change in pain sensitivity was observed in control males following LPS exposure. No difference in response was observed between the female PE and control offspring on the von Frey test, however PE female offspring displayed increased thresholds on the tail immersion test compared to baseline - an effect not observed in the control female offspring. Pain sensitivity on the hot plate test was unaffected by prenatal exposure to endotoxin. These data suggest that prenatal exposure to products associated with bacterial infection have the capacity to alter pain responses, which are evident in the adult offspring., (Copyright 2010 Elsevier Inc. All rights reserved.)

Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1(-/-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488-499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected.

Panic disorder is characterized by both specific, phased fear and generalized, chronic anxiety. Standard extinction procedures are efficient in reducing specific fear. However, methods based on human conditioning research - that are capable of reducing chronic anxiety have not yet been thoroughly investigated. This study evaluates a new way of reducing chronic anxiety by signaling aversive events (or by making them more predictable). Using an experimental approach with healthy participants, specific fear and chronic anxiety were operationalized in a within-subjects fear-potentiated startle paradigm by, respectively, conditioning to a cue by presenting predictable shocks and conditioning to a context induced by unpredictable shocks. The results clearly demonstrate that context conditioning is reduced when a discrete cue is added that predicts the onset of the aversive event. The data suggest that making unpredictable events, such as for example panic attacks, predictable, may reduce the generalized and sustained anxiety that often complicates exposure treatment.

Fear conditioning studies have shown that social anxiety is associated with enhanced expectancy of aversive outcome. However, the relation between cognitive expectancy and social anxiety has never been tested in avoidance conditioning paradigms. We compared 48 low (LSA) and high socially anxious individuals (HSA) on subjective expectancy of aversive outcome during an avoidance conditioning task. Displays of neutral faces were coupled with an aversive outcome (US): a shout and a shock. Participants could avoid the US by pressing a correct button from a button box. First, HSA showed higher US expectancy than LSA during the initial phase of avoidance conditioning, supporting the view that socially anxious individuals have an expectancy bias when social situations are ambiguous. Second, when the avoidance response became unavailable, LSA showed lower US expectancy than HSA, suggesting that low socially anxious individuals are prone to a positive bias when perceived threat is high. A lack of such positive bias in socially anxious individuals may lead to higher susceptibility to safety behavior interpretations. Together, these findings support the role of cognitive processes in avoidance conditioning and underscore the relevance to encounter avoidance learning when studying social anxiety.

Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discriminative learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger cues. Importantly, this discrimination deficit was driven by enhanced startle-potentiation to the learned safety cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety cues.

Though generalization of conditioned fear has been implicated as a central feature of pathological anxiety, surprisingly little is known about the psychobiology of this learning phenomenon in humans. Whereas animal work has frequently applied methods to examine generalization gradients to study the gradual weakening of the conditioned-fear response as the test stimulus increasingly differs from the conditioned stimulus (CS), to our knowledge no psychobiological studies of such gradients have been conducted in humans over the last 40 years. The current effort validates an updated generalization paradigm incorporating more recent methods for the objective measurement of anxiety (fear-potentiated startle). The paradigm employs 10, quasi-randomly presented, rings of gradually increasing size with extremes serving as CS+ and CS-. The eight rings of intermediary size serve as generalization stimuli (GSs) and create a continuum-of-similarity from CS+ to CS-. Both startle data and online self-report ratings demonstrate continuous decreases in generalization as the presented stimulus becomes less similar to the CS+. The current paradigm represents an updated and efficacious tool with which to study fear generalization--a central, yet understudied conditioning-correlate of pathologic anxiety.

The cognitive model of social anxiety predicts that negative self-focused cognitions increase anxiety when anticipating social threat. To test this prediction, 36 individuals were asked to anticipate and perform a public-speaking task. During anticipation, negative self-focused cognitions or relaxation were experimentally induced while self-reported anxiety, autonomic arousal (heart rate, heart rate variability, skin conductance level), and acoustic eye-blink startle response were assessed. As predicted, negative self-focused cognitions mediated the effects of trait social anxiety on self-reported anxiety and heart rate variability during negative anticipation. Furthermore, trait social anxiety predicted increased startle amplitudes. These findings support a central assumption of the cognitive model of social anxiety.

We examined the interaction between a form of subjective emotional reactivity (perceived coping) and physiological reactivity in relation to risk for substance use disorders. Skin conductance responses to unpredictable white noise blasts were collected from 110 men and women who also rated their perceived coping to the blasts and underwent semi-structured interviews to assess psychiatric symptoms. Reported inability to cope in conjunction with low skin conductance reactivity were related to higher symptom counts of alcohol and cannabis use disorders as well as antisocial personality disorder symptoms. The findings highlight the potential importance of the interface between cognitive/emotional and physiological processes as they relate to risk for substance use disorders and perhaps other externalizing disorders.

Men and women may differ in their sensitivity to the mood-modulating properties of nicotine. Male and female adult smokers were exposed to four sessions crossing two nicotine deprivation conditions (12-h deprived vs. nondeprived) with two drug conditions (nicotine vs. placebo nasal spray). Acoustic probes elicited startle eyeblink responses while viewing affective and cigarette-related slides. In-session mood ratings were collected to gauge self-reported negative affect, positive affect, and craving. Nicotine nasal spray reduced startle amplitude in both men and women following 12-h deprivation compared with smoking nondeprivation. During nondeprivation, nicotine nasal spray increased startle amplitude in women compared with placebo spray, whereas no difference was found for men. The startle results suggest that both men and women are responsive to the hedonic properties of nicotine.